Time‐restricted feeding improves the reproductive function of female mice via liver fibroblast growth factor 21

Background There has been a significant increase, to epidemic levels, of obese and overweight women of reproductive age, causing impairments to reproductive health. Time‐restricted feeding (TRF) including isocaloric intake has shown to be preventive of obesity‐related disorders. However, its therapeutic ability to improve the reproductive function of female remains largely unknown. Methods Here, we investigated the ability of TRF to improve the reproductive function in wild‐type and liver‐specific FGF21 knockout female mice. To study fertility, a continuous and a short‐term fertility test, gonadotropin releasing‐hormone (GnRH), and Kisspeptin test were performed. Immortalized GnRH neuron was used to examine the direct role of liver fibroblast growth factor 21 (FGF21) on GnRH secretion. Results We found that TRF rescues female mice from bodyweight gain and glucose intolerance, as well as ovarian follicle loss and dysfunction of estrus cyclicity induced by high‐fat diet. Furthermore, the beneficial effects of the TRF regimen on the reproductive performance were also observed in mice fed both chow and high‐fat diet. However, those beneficial effects of TRF on metabolism and reproduction were absent in liver‐specific FGF21 knockout mice. In vitro, FGF21 directly acted on GnRH neurons to modulate GnRH secretion via extracellular regulated protein kinases (ERK1/2) pathway. Conclusions Overall, time‐restricted feeding improves the reproductive function of female mice and liver FGF21 signaling plays a key role in GnRH neuron activity in female mice. Time‐restricted feeding increased fertility. Time‐restricted feeding prevented hypothalamic hypogonadism. FGF21 modulated GnRH secretion via ERK1/2 pathway. Liver FGF21 signaling was involved in the beneficial effect of time‐restricted feeding on fertility.